Oasi Research Institute-IRCCS, 94018 Troina, Italy.
Department Biological, Geological and Environmental Sciences, University of Catania, Via Androne 81, 95124 Catania, Italy.
Genes (Basel). 2024 Feb 27;15(3):306. doi: 10.3390/genes15030306.
The UNC-5 family of netrin receptor genes, predominantly expressed in brain tissues, plays a pivotal role in various neuronal processes. Mutations in genes involved in axon development contribute to a wide spectrum of human diseases, including developmental, neuropsychiatric, and neurodegenerative disorders. The NTN1/DCC signaling pathway, interacting with UNC5C, plays a crucial role in central nervous system axon guidance and has been associated with psychiatric disorders during adolescence in humans. Whole-exome sequencing analysis unveiled two compound heterozygous causative mutations within the gene in a patient diagnosed with psychiatric disorders. In silico analysis demonstrated that neither of the observed variants affected the allosteric linkage between UNC5C and NTN1. In fact, these mutations are located within crucial cytoplasmic domains, specifically ZU5 and the region required for the netrin-mediated axon repulsion of neuronal growth cones. These domains play a critical role in forming the supramodular protein structure and directly interact with microtubules, thereby ensuring the functionality of the axon repulsion process. We emphasize that these mutations disrupt the aforementioned processes, thereby associating the gene with psychiatric disorders for the first time and expanding the number of genes related to psychiatric disorders. Further research is required to validate the correlation of the gene with psychiatric disorders, but we suggest including it in the genetic analysis of patients with psychiatric disorders.
UNC-5 家族的神经导向因子受体基因主要在脑组织中表达，在各种神经元过程中发挥关键作用。参与轴突发育的基因发生突变会导致广泛的人类疾病，包括发育性、神经精神性和神经退行性疾病。与 UNC5C 相互作用的 NTN1/DCC 信号通路在中枢神经系统轴突导向中发挥着关键作用，并与人类青春期的精神疾病有关。全外显子组测序分析在一名被诊断为精神疾病的患者中发现了 基因内的两个复合杂合性致病突变。计算机分析表明，观察到的变异都没有影响 UNC5C 和 NTN1 之间的变构连接。事实上，这些突变位于关键的细胞质结构域内，特别是 ZU5 和神经导向因子介导的神经元生长锥轴突排斥所需的区域。这些结构域在形成超模块蛋白结构中起着关键作用，并直接与微管相互作用，从而确保轴突排斥过程的功能。我们强调，这些突变破坏了上述过程，首次将 基因与精神疾病联系起来，并扩大了与精神疾病相关的基因数量。需要进一步的研究来验证 基因与精神疾病的相关性，但我们建议将其纳入精神疾病患者的基因分析中。
